Biomedical subjects

Prashant V Desai

Publications and source records attributed to Prashant V Desai.

10 recordsLinked to original sources

PubMed2006

Ligand-supported homology modeling of the human angiotensin II type 1 (AT(1)) receptor: insights into the molecular determinants of telmisartan binding.

Angiotensin II type 1 (AT(1)) receptor belongs to the super-family of G-protein-coupled receptors, and antagonists of the AT(1) receptor are effectively used in the treatment of hypertension. To understand the molecular interactions of these antagonists, such as losartan and telmisartan, with the AT(1) receptor, a homology model of the human AT(1) (hAT(1)) receptor with all connecting loops was constructed from the 2.6 A resolution crystal structure (PDB i.d., 1L9H) of bovine rhodopsin. The initial model generated by MODELLER was subjected to a stepwise ligand-supported model refinement. This protocol involved initial docking of non-peptide AT(1) antagonists in the putative binding site, followed by several rounds of iterative energy minimizations and molecular dynamics simulations. The final model was validated based on its correlation with several structure-activity relationships and site-directed mutagenesis data. The final model was also found to be in agreement with a previously reported AT(1) antagonist pharmacophore model. Docking studies were performed for a series of non-peptide AT(1) receptor antagonists in the active site of the final hAT(1) receptor model. The docking was able to identify key molecular interactions for all the AT(1) antagonists studied. Reasonable correlation was observed between the interaction energy values and the corresponding binding affinities of these ligands, providing further validation for the model. In addition, an extensive unrestrained molecular dynamics simulation showed that the docking-derived bound pose of telmisartan is energetically stable. Knowledge gained from the present studies can be used in structure-based drug design for developing novel ligands for the AT(1) receptor.

Amino Acid Sequence↗

PubMed2006

Design and synthesis of the first generation of dithiolane thiazolidinedione- and phenylacetic acid-based PPARgamma agonists.

A series of novel derivatives of potent antioxidant vitamin, alpha-lipoic acid, and related analogues were designed, synthesized, and evaluated for their PPARgamma agonist activities. Compounds 9a and the water soluble analogue11e were found to be potent PPARgamma agonists. Compound 9a appeared to have a significant role in improving insulin sensitivity and reducing triglyceride levels in fa/fa rats as well as inhibited proliferation of a variety of normal and neoplastic cultured human cell types. These novel compounds may prove efficacious not only in the treatment of Type 2 diabetes, but also atherosclerosis, prevention of vascular restenosis, and inflammatory skin diseases.

Adipocytes↗

PubMed2006

Identification of novel parasitic cysteine protease inhibitors by use of virtual screening. 2. The available chemical directory.

The incidence of parasitic infections such as malaria, leishmaniasis, and trypanosomiasis has been steadily increasing. Since the existing chemotherapy of these diseases suffers from lack of safe and effective drugs and/or the presence of widespread drug resistance, there is an urgent need for development of potent, mechanism-based antiparasitic agents against these diseases. Cysteine proteases have been established as valid targets for this purpose. The Available Chemical Directory consisting of nearly 355,000 compounds was screened in silico against the homology models of plasmodial cysteine proteases, falcipain-2, and falcipain-3, to identify structurally diverse non-peptide inhibitors. The study led to identification of 22 inhibitors of parasitic cysteine proteases out of which 18 compounds were active against falcipain-2 and falcipain-3. Eight compounds exhibited dual activity against both enzymes. Additionally, four compounds were found to inhibit L. donovani cysteine protease. While one of the cysteine protease inhibitors also exhibited in vitro antiplasmodial activity with an IC50 value of 9.5 microM, others did not show noticeable antiplasmodial activity up to 20 microM. A model identifying important pharmacophoric features common to the structurally diverse falcipain-2 inhibitors has also been developed. Very few potent non-peptide inhibitors of the parasitic cysteine proteases have been reported so far, and identification of these novel and chemically diverse inhibitors should provide leads to be optimized into candidates to treat protozoal infections.

Animals↗

PubMed2006

Bioassay for the identification of natural product-based activators of peroxisome proliferator-activated receptor-gamma (PPARgamma): the marine sponge metabolite psammaplin A activates PPARgamma and induces apoptosis in human breast tumor cells.

Peroxisome proliferator-activated receptors (PPARs), members of the nuclear hormone receptor (NHR) family, are ligand-activated transcription factors. Ligands (agonists) of PPARgamma have been shown to inhibit growth, promote terminal differentiation, and induce apoptosis in human breast tumor cells. A cell-based reporter assay was developed to examine extracts of terrestrial and marine organisms for the ability to activate PPARgamma. Bioassay-guided fractionation and isolation of an active extract from Pseudoceratina rhax yielded the known histone deacetylase (HDAC) inhibitor psammaplin A (1). Compound 1 activates PPARgamma in a MCF-7 cell-based reporter assay and induces apoptosis in human breast tumor cells in vitro. Molecular modeling studies suggest that 1 may interact with binding sites within the PPARgamma ligand-binding pocket. Therefore, in addition to its known effects on HDAC-mediated processes, activation of PPARgamma-regulated gene expression may play a role in the ability of 1 to induce apoptosis.

Animals↗

PubMed2006

Homology modeling of G-protein-coupled receptors and implications in drug design.

G-protein-coupled receptors (GPCRs) are considered therapeutically important due to their involvement in a variety of processes governing several cellular functions, and their tractability as drug targets. A large percentage of drugs on the market, and in development stages, target the super family of the GPCRs. The enormous interest in GPCR drug design is, however, limited by the scarcity of structural information. The only GPCR for which a three dimensional (3D) structure is reported is bovine rhodopsin and it belongs to class A of the GPCR family. As a result, there has been considerable interest in alternative techniques, for example, homology modeling of GPCRs, in order to derive useful three dimensional models of other proteins for use in structure-based drug design. However, homology modeling of GPCRs is not straightforward, and encounters several problems, owing to the availability of a single structural template, as well as the low degree of sequence homology between the template and target sequences. There are several key issues which need to be considered during every stage of GPCR homology modeling, in order to derive reasonable 3D models. Homology modeling of GPCRs has been utilized increasingly in the past few years and has been successful, not only in furthering the understanding of ligand-protein interactions, but also in the identification of new and potent ligands. Thus, with the lessons learned from past experiences and new developments, homology modeling in case of GPCRs can be harnessed for developing more reliable three dimensional models. This, in turn, will provide better tools to use in structure-based drug design leading to the identification of novel and potent GPCR ligands for several therapeutic indications.

Amino Acid Sequence↗

PubMed2004

Identification of novel parasitic cysteine protease inhibitors using virtual screening. 1. The ChemBridge database.

Trypanosomiasis, leishmaniasis, and malaria are major parasitic diseases in developing countries. The existing chemotherapy of these diseases suffers from lack of safe and effective drugs and/or the presence of widespread drug resistance. Cysteine proteases are exciting novel targets for antiparasitic drug design. Virtual screening was performed in an attempt to identify novel druglike nonpeptide inhibitors of parasitic cysteine proteases. The ChemBridge database consisting of approximately 241 000 compounds was screened against homology models of falcipain-2 and falcipain-3 in three consecutive stages of docking. A total of 24 diverse inhibitors were identified from an initial group of 84, of which 12 compounds appeared to be dual inhibitors of falcipain-2 and falcipain-3. Four compounds showed inhibition of both the malarial cysteine proteases as well as Leishmania donovani cysteine protease.

Animals↗

PubMed2004

An alpha-proteobacterial type malate dehydrogenase may complement LDH function in Plasmodium falciparum. Cloning and biochemical characterization of the enzyme.

Malate dehydrogenase (MDH) may be important in carbohydrate and energy metabolism in malarial parasites. The cDNA corresponding to the MDH gene, identified on chromosome 6 of the Plasmodium falciparum genome, was amplified by RT-PCR, cloned and overexpressed in Escherichia coli. The recombinant Pf MDH was purified to homogeneity and biochemically characterized as an NAD(+)(H)-specific MDH, which catalysed reversible interconversion of malate to oxaloacetate. Pf MDH could not use NADP/NADPH as a cofactor, but used acetylpyridine adenine dinucleoide, an analogue of NAD. The enzyme exhibited strict substrate and cofactor specificity. The highest levels of Pf MDH transcripts were detected in trophozoites while the Pf MDH protein level remained high in trophozoites as well as schizonts. A highly refined model of Pf MDH revealed distinct structural characteristics of substrate and cofactor binding sites and important amino acid residues lining these pockets. The active site amino acid residues involved in substrate binding were conserved in Pf MDH but the N-terminal glycine motif, which is involved in nucleotide binding, was similar to the GXGXXG signature sequence found in Pf LDH and also in alpha-proteobacterial MDHs. Oxamic acid did not inhibit Pf MDH, while gossypol, which interacts at the nucleotide binding site of oxidoreductases and shows antimalarial activity, inhibited Pf MDH also. Treatment of a synchronized culture of P. falciparum trophozoites with gossypol caused induction in expression of Pf MDH, while expression of Pf LDH was reduced and expression of malate:quinone oxidoreductase remained unchanged. Pf MDH may complement Pf LDH function of NAD/NADH coupling in malaria parasites. Thus, dual inhibitors of Pf MDH and Pf LDH may be required to target this pathway and to develop potential new antimalarial drugs.

Amino Acid Sequence↗

PubMed2003

Structure-activity relationships of the antimalarial agent artemisinin. 8. design, synthesis, and CoMFA studies toward the development of artemisinin-based drugs against leishmaniasis and malaria.

Artemisinin (1) and its analogues have been well studied for their antimalarial activity. Here we present the antimalarial activity of some novel C-9-modified artemisinin analogues synthesized using artemisitene as the key intermediate. Further, antileishmanial activity of more than 70 artemisinin derivatives against Leishmania donovani promastigotes is described for the first time. A comprehensive structure-activity relationship study using CoMFA is discussed. These analogues exhibited leishmanicidal activity in micromolar concentrations, and the overall activity profile appears to be similar to that against malaria. Substitution at the C-9beta position was shown to improve the activity in both cases. The 10-deoxo derivatives showed better activity compared to the corresponding lactones. In general, compounds with C-9alpha substitution exhibited lower antimalarial as well as antileishmanial activities compared to the corresponding C-9beta analogues. The importance of the peroxide group for the observed activity of these analogues against leishmania was evident from the fact that 1-deoxyartemisinin analogues did not exhibit antileishmanial activity. The study suggests the possibility of developing artemisinin analogues as potential drug candidates against both malaria and leishmaniasis.

Animals↗

PubMed2003

Probing the structure of falcipain-3, a cysteine protease from Plasmodium falciparum: comparative protein modeling and docking studies.

Increasing resistance of malaria parasites to conventional antimalarial drugs is an important factor contributing to the persistence of the disease as a major health threat. The ongoing search for novel targets has resulted in identification and expression of several enzymes including cysteine proteases that are implicated in hemoglobin degradation. Falcipain-2 and falcipain-3 are considered to be the two principal cysteine proteases in this degradation, and hence, are potential drug targets. A homology model of falcipain-3 was built and validated by various structure/geometry verification tools as well as docking studies of known substrates. The correlation coefficient of 0.975 between interaction energies and K(m) values of these substrates provided additional support for the model. On comparison with the previously reported falcipain-2 homology model, the currently constructed falcipain-3 structure showed important differences between the S2 pockets that might explain the variations in the K(m) values of various substrates for these enzymes. Further, docking studies also provided insight into possible binding modes and interactions of ligands with falcipain-3. Results of the current study could be employed in de novo drug design leading to development of new antimalarial agents.

Amino Acid Sequence↗

PubMedDate not supplied

A 3D-QSAR of angiotensin II (AT1) receptor antagonists based on receptor surface analysis.

A hypothetical receptor surface model has been constructed for a set of 38 AT1 antagonists using activity data of each molecule as a weight in the building of the receptor surface. The best model was derived by optimizing various parameters such as atomic partial charges, surface fit, and the manner of representation of electrostatics on the surface. Descriptors such as van der Waals energy, electrostatic energy, and total nonbonded energy were used individually or in combination to derive a family of quantitative structure-activity relationship equations using G/PLS as the statistical method.

Angiotensin I↗